Tetrahydroquinoline derivatives as stat6-modulators, preparation and use thereof

ABSTRACT

Compounds of formula (I) are modulators of STAT6 signal pathway activity, and can be used in the treatment of atopic dermatitis, urticaria, allergic asthma, allergic rhinitis, a food allergy, allergic conjunctivitis, hayfever, bullous pemphigoid, industrial sensitization, chronic rejection of transplants or COPD

The present invention relates to tetrahydroquinoline derivatives which are modulators of the Signal Transducer and Activator of Transcription 6 (STAT6) pathway, to processes for their preparation, to pharmaceutical compositions comprising them and to methods of using them (for example for the treatment of STAT6-mediated diseases).

STATs are proteins involved in signal transduction from cytokine and growth factor receptors. STAT6 binds to specific phosphotyrosine motifs on an activated IL4/IL-13 receptor α-chain. Once bound, the protein is phosphorylated by JAK kinases and then STAT6 forms a homodimer that translocates into the nucleus and stimulates gene transcription. Gene knockout studies in mice have shown that STAT6 is required for IL-4/IL-13 responses that have pathological consequences in allergic disease, namely IgE production and differentiation of T helper cells to the Th2 phenotype. (Linehan L A. Warren W D. Thompson P A. Grusby M J. Berton M T. STAT6 is required for IL4-induced germline Ig gene transcription and switch recombination. Journal of Immunology. 161(1):302–10, 1998; Kaplan M H. Schindler U. Smiley S T. Grusby M J. Stat6 is required for mediating responses to IL4 and for development of Th2 cells. Immunity. 4(3):313–9, 1996; Malabarba M G. Rui H. Deutsch H H. Chung J. Kalthoff F S. Farrar W L. Kirken R A. Interleukin-13 is a potent activator of JAK3 and STAT6 in cells expressing interleukin-2 receptor-gamma and interleukin-4 receptor-alpha. Biochemical Journal. 319 (Pt 3):865–72, 1996.)

Interference with STAT6 activation would be expected to reduce the production of proinflamatory cytokines like IL-4 and IL-5. A compound antagonizing STAT6 would, therefore, be expected to have utility in treating disease states such as asthma, dermatitis (allergic and atopic), urticaria, rhinitis and/or COPD.

1,2,3,4-Tetrahydroquinolines are disclosed in WO 00/17165 and WO 00/17166.

The present invention provides a compound of formula (I):

wherein:

-   L is CH₂, O or S; -   n is 0 or 1; -   W, Y and Z are, independently hydrogen, cyano, nitro, halogen, N₃,     C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆     alkylthio, C₃₋₆ cycloalkyl, CO₂H, CO₂(C₁₋₆ alkyl), CONR⁵R⁶, COR¹⁰,     SO₂R¹², methylenedioxy, NHCOR¹¹ or heterocyclyl; -   R² is aryl or heteroaryl optionally substituted by cyano, nitro,     halogen, N₃, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆     haloalkoxy, C₁₋₆ alkylthio, C₃₋₆ cycloalkyl, CO₂H, CO₂(C₁₋₆ alkyl),     CONR³R¹⁴, COR¹⁵, SO₂R¹⁶, methylenedioxy, NHCOR¹⁷ or heterocyclyl; -   R³ is C₁₋₄ alkyl or C₁₋₄ haloalkyl; -   R⁴ is CO(C₁₋₄ alkyl) or CO(C₁₋₄ haloalkyl); -   X is O, S, SO, SO₂, CR⁷R⁸ or NR⁹; -   R⁵, R⁶, R⁷, R⁸, R¹³ and R¹⁴ are, independently, hydrogen or C₁₋₆     alkyl; -   R⁹ is hydrogen, C₁₋₆ alkyl or CO(C₁₋₄ alkyl); -   R¹⁰, R¹¹, R¹², R¹⁵, R¹⁶ and R¹⁷ are, independently, C₁₋₆ alkyl or     phenyl; -   or a pharmaceutically acceptable salt thereof; or a solvate thereof;     provided that the compound of formula (I) is not a compound of     formula (Iz):

(Iz)

wherein R^(1b) R^(1d) R^(1c) R^(4′) R² R⁹ H H H n-butyl C₆H₅ H H H H n-propyl C₆H₅ COCH₃ H H H n-propyl C₆H₅ H H H H Ethyl C₆H₅ H Br H H Methyl C₆H₅ COCH₃ Methyl H H Methyl 4-CH₃—C₆H₄ H Methyl Methyl H Methyl 2,4-(CH₃)₂—C₆H₃ H H H H Methyl C₆H₅ H NO₂ H H Methyl 4-NO₂—C₆H₄ COCH₃ NO₂ H H Methyl C₆H₅ COCH₃ Cl H H Methyl C₆H₅ COCH₃ H H H Methyl C₆H₅ COCH₃ H H H Methyl 2,4-Br₂—C₆H₃ COCH₃ in free base or unsolvated form.

Alkyl groups are straight or branched chain and are, for example, methyl, ethyl, n-propyl, iso-propyl or n-butyl. Alkoxy is, for example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy or tert-butoxy.

Cycloalkyl is, for example, cyclopropyl, cyclopentyl or cyclohexyl.

Halogen includes chlorine, fluorine and bromine.

Haloalkyl groups peferably comprise fluorine, chlorine or bromine atoms, and haloalkyl is, for example, CF₃, while haloalkoxy is, for example, OCF₃.

Aryl is, for example, phenyl or naphthyl.

Heteroaryl is, for example, an aromatic monocyclic 5- or 6-membered ring comprising one, two or three heteroatoms selected from the group comprising nitrogen, oxygen and sulphur. Heteroaryl is, for example, pyridine, pyridazine, pyrimidine, pyrazine, pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, furan, thiophene, oxazole, is isoxazole, thiazole or isothiazole.

Heterocyclyl is a 5- or 6-membered ring comprising one or two nitrogen atoms and, optionally, one oxygen or sulphur atom. Heterocyclyl is, for example, morpholinyl, piperidinyl or pyrrolidinyl. Heterocyclyl may also be thiomorpholinyl. Heterocyclyl is optionally substituted by C₁₋₄ alkyl.

Salts of the compounds of formula (I) are preferably pharmaceutically acceptable salts. Pharmaceutically acceptable salts of compounds of the present invention are, for example, acid addition salts (such as hydrochloride, hydrobromide or acetate salts).

Solvates of the compounds or salts of the present invention are conveniently hydrates, such as monohydrates or dihydrates.

Compounds of the present invention include all stereoisomers and mixtures thereof in all proportions.

In one particular aspect the present invention provides a compound of formula (I):

wherein: L is CH₂, O or S; n is 0 or 1; W, Y and Z are, independently hydrogen, cyano, nitro, halogen, N₃, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkylthio, C₃₋₆ cycloalkyl, CO₂H, CO₂(C₁₋₆ alkyl), CONR⁵R⁶, COR¹⁰, SO₂R¹², methylenedioxy, NHCOR¹¹ or heterocyclyl; R² is aryl or heteroaryl optionally substituted by cyano, nitro, halogen, N₃, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkylthio, C₃₋₆ cycloalkyl, CO₂H, CO₂(C₁₋₆ alkyl), CONR¹³R¹⁴, COR¹⁵, SO₂R¹⁶, methylenedioxy, NHCOR¹⁷ or heterocyclyl; R³ is C₁₋₄ alkyl or C₁₋₄ haloalkyl; R⁴ is CO(C₁₋₄ alkyl) or CO(C₁₋₄ haloalkyl); X is O, S, SO, SO₂, CR⁷R⁸ or NR⁹; R⁵, R⁶, R⁷, R⁸, R¹³ and R¹⁴ are, independently, hydrogen or C₁₋₆ alkyl; R⁹ is hydrogen, C₁₋₆ alkyl or CO(C₁₋₄ alkyl); R¹⁰, R¹¹, R¹², R¹⁵, R¹⁶ and R¹⁷ are, independently, C₁₋₆ alkyl or phenyl; or a pharmaceutically acceptable salt thereof; or a solvate thereof; provided that the compound of formula (I) is not a compound of formula (Iz):

(Iz)

wherein R^(1b) R^(1d) R^(1c) R^(4′) R² R⁹ H H H n-butyl C₆H₅ H H H H n-propyl C₆H₅ COCH₃ H H H n-propyl C₆H₅ H H H H Ethyl C₆H₅ H Br H H Methyl C₆H₅ COCH₃ Methyl H H Methyl 4-CH₃—C₆H₄ H Methyl Methyl H Methyl 2,4- H (CH₃)₂—C₆H₃ H H H Methyl C₆H₅ H NO₂ H H Methyl 4-NO₂—C₆H₄ COCH₃ NO₂ H H Methyl C₆H₅ COCH₃ Cl H H Methyl C₆H₅ COCH₃ H H H Methyl C₆H₅ COCH₃ H H H Methyl 2,4-Br₂—C₆H₃ COCH₃ H H Methyl Methyl 4-C₂H₅—C₆H₄ H H H H Methyl C₆H₅ CO-n- propyl H H H Methyl C₆H₅ CO-t-butyl H H H CH₃CH—CH₃ C₆H₅ H H H H CF₃ C₆H₅ COCF₃ H H H Ethyl C₆H₅ COCH₃ H H H iso-Pr C₆H₅ COCH₃ H H H iso-Pr C₆H₅ H H H H Methyl C₆H₅ CO-n- butyl H H H Methyl C₆H₅ CO-ethyl H H H n-butyl C₆H₅ COCH₃ H H H Methyl C₆H₅ CO-i- propyl H H H Ethyl C₆H₅ CO-ethyl H H H CH₃CH₂ C₆H₅ H in free base or unsolvated form.

In another aspect of the invention W and Y are both hydrogen. In yet another aspect W, Y and Z are, independently, for example, hydrogen, chloro, cyano, CO₂(C₁₋₄ alkyl) (such as CO₂Me or CO₂Et) or C₁₋₄ alkoxy (such as methoxy).

In a further aspect R² is, for example, optionally substituted phenyl, such as phenyl optionally substituted by chloro, cyano, CO₂(C₁₋₄ alkyl) (such as CO₂Me or CO₂Et) or C₁₋₄ alkoxy (such as methoxy).

The variable R³ is, for example methyl or ethyl; but is preferably methyl.

The variable R⁴ is, for example, acetyl.

The variable X is, for example, NR⁹, wherein R⁹ is hydrogen or COMe.

It is preferred that L is CH₂ and that n is 1.

In a still further aspect the present invention provides a compound of formula (Ia):

wherein Z, R³, R⁴ and X are as hereinbefore defined, and R^(2c) is hydrogen, cyano, nitro, is halogen, N₃, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkylthio, C₃₋₆ cycloalkyl, CO₂H, CO₂(C₁₋₆ alkyl), CONR¹³R¹⁴, COR¹⁵, SO₂R¹⁶, methylenedioxy, NHCOR¹⁷ or heterocyclyl; wherein R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are as defined above, or a pharmaceutically acceptable salt thereof; or a solvate thereof.

In another aspect the present invention provides a compound of formula (Ia) wherein Z and R^(2c) are independently selected from the group consisting of: hydrogen, C(O)₂CH₃, iodo, N₃, bromo, methyl, C(O)₂CH₂CH₃, cyano and methoxy; provided that Z and R^(2c) are not both hydrogen or methyl.

In yet another aspect the present invention provides a compound of formula (Ia) wherein R³ is methyl; R⁴ is C(O)CH₃; and X is NH; and: Z and R^(2c) are both CO₂CH₃; or Z is iodo and R^(2c) is hydrogen; or Z and R^(2c) are both iodo; or Z and R^(2c) are both N₃; or Z and R^(2c) are both bromo; Z and R^(2c) are both CO₂CH₂CH₃; or Z is hydrogen and R^(2c) is cyano; or Z is methoxy and R^(2c) is CO₂CH₃.

In a further aspect the present invention provides a compound of formula (Ib):

wherein R², R³, R⁴, X, Y and Z are as hereinbefore defined, or a pharmaceutically acceptable salt thereof; or a solvate thereof.

In a further aspect the present invention provides a compound of formula (I) wherein the relative configuration of the 2- and 4-position stereocentres is Z with the absolute configuration as depicted in formula (Ib). In a still further aspect the present invention provides a compound of formula (Ib) having an absolute configuration (2S, 4R) and wherein X is NH, R³ is methyl, R⁴ is COCH₃ and W, Y, Z and R² are as defined above.

In another aspect of the present invention W and Y are both hydrogen and Z is hydrogen, C(O)₂CH₃, iodo, N₃, bromo, methyl, C(O)₂CH₂CH₃, cyano or methoxy.

In a further aspect of the present invention R² is phenyl para-substituted by C(O)₂CH₃, iodo, N₃, bromo, methyl, C(O)₂CH₂CH₃, cyano or methoxy.

In a further aspect the present invention provides a compound of formula (Ic) wherein the substituent R³ is cis to the substituted amine group at the 4 position of the tetrahydroquinoline:

wherein R³, R⁴ and R⁹ are as hereinbefore defined;

-   R^(1b) is H, halogen, N₃, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio,     C₃₋₆ cycloalkyl, CO₂H, CO₂(C₁₋₆ alkyl), COC₁₋₆ alkyl, SO₂Me or     morpholin-4-yl; -   R^(1d) is H or Me; -   R^(2a) is H, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy or CONH₂; -   R^(2b) is H, halogen, C₁₋₆ alkyl, or methylenedioxy; -   R^(2c) is H, cyano, halogen, N₃, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆     alkylthio, C₃₋₆ cycloalkyl, CO₂H, CO₂(C₁₋₆ alkyl), CONH₂, COC₁₋₆     alkyl, SO₂Me, methylenedioxy, NHCOMe or heterocyclyl; and -   R^(2d) is H, C₁₋₆ alkyl, or halogen, -   or a pharmaceutically acceptable salt thereof; or a solvate thereof.

In a still further aspect the present invention provides a compound of formula (Id):

wherein wherein R^(1b), R^(1d), R^(2a), R^(2b), R^(2c), R^(2d), R³, R⁴ and R⁹ are as hereinbefore defined; R^(1a) is H or C₁₋₆ alkyl; and R^(1c) is H or C₁₋₆ alkyl; or a pharmaceutically acceptable salt thereof; or a solvate thereof.

In another aspect the present invention provides a compound of formula (Ie):

wherein R^(1b) is H, Cl or CH₃; X is NH, S, or CH₂; and R² is pyrazin-2-yl or phenyl; or a pharmaceutically acceptable salt thereof; or a solvate thereof.

Compounds of formulae (Ia), (Ib), (Ic), (Id) and (Ie) are sub-groups of compounds of formula (I).

The following Tables provide examples of compounds of the invention. Table I illustrates compounds of formula (Ic); Table II illustrates compounds of formula (Id); and Table III illustrates compounds of formula (Ie).

TABLE I Compound R^(1b) R^(1d) R^(2a) R^(2b) R^(2c) R^(2d) R³ R⁴ R⁹ 1 H H H H H H Me COMe H 2 OMe H H H OMe H Me COMe H 3 Cl H H H Cl H Me COMe H 4 iso-Pr H H H iso-Pr H Me COMe H 5 I H H H I H Me COMe H 6 Br H H H Br H Me COMe H 7 F H H H F H Me COMe H 8 H H H H H H Me COMe COMe 9 Me H H H Me H Me COMe H 10 Et H H H Et H Me COMe H 11 cyclohexyl H H H cyclohexyl H Me COMe H 12 n-Bu H H H n-Bu H Me COMe H 13 SMe H H H SMe H Me COMe H 14 OMe H H H OMe H Me COMe COMe 15 Me H H H Me H Me COEt H 16 N₃ H H H N₃ H Me COMe H 17 CO₂H H H H CO₂H H Me COMe H 18 CO₂Me H H H CO₂Me H Me COMe H 19 H H Cl H H H Me COMe H 20 H H H Cl H H Me COMe H 21 H H H H Cl H Me COMe H 22 H H H H Br H Me COMe H 23 H H H H I H Me COMe H 24 H H OMe H H H Me COMe H 25 H H H H OMe H Me COMe H 26 H H H Me H H Me COMe H 27 H H H H Me H Me COMe H 28 H H Cl H Me H Me COMe H 29 H H Me H Cl H Me COMe H 30 H H Cl Cl H H Me COMe H 31 H H Cl H Cl H Me COMe H 32 H H Cl H H Cl Me COMe H 33 H H H Cl Cl H Me COMe H 34 H H H Cl H Cl Me COMe H 35 H H H H cyclohexyl H Me COMe H 36 H H H H CN H Me COMe H 37 H H H Methylenedioxy H Me COMe H 38 Cl H H H Me H Me COMe H 39 Cl H H H Morpholin-4-yl H Me COMe H 40 Me H H H OMe H Me COMe H 41 Cl H H H OMe H Me COMe H 42 CO₂Et H H H CO₂Et H Me COMe H 43 H H H H CN H Et COMe H 44 CO₂CHMe₂ H H H CO₂CHMe₂ H Me COMe H 45 OMe H H H Cl H Me COMe H 46 OMe H H H Me H Me COMe H 47 OMe H H H Benzoyl H Me COMe H 48 Cl H H H CO₂Me H Me COMe H 49 OMe H H H COMe H Me COMe H 50 OMe H H H CONH₂ H Me COMe H 51 OMe H H H CN H Me COMe H 52 OMe H H H CO₂Me H Me COMe H 53 H Me H H CN H Me COMe H 54 OMe H H H Morpholin-4-yl H Me COMe H 55 Cl H CONH₂ H H H Me COMe H 56 H H H H CONH₂ H Me COMe H 57 Me H H H CN H Me COMe H 58 Me H H H Morpholin-4-yl H Me COMe H 59 H H CONH₂ H H H Me COMe H 60 H H H H NHCOMe H Me COMe H 61 Cl H H H NHCOMe H Me COMe H 62 H H H H CO₂Me H Me COMe H 63 OMe H H H NHCOMe H Me COMe H 64 OMe H H H SO₂Me H Me COMe H 65 Br H H H Benzoyl H Me COMe H 66 Morpholin-4-yl H H H OMe H Me COMe H 67 Morpholin-4-yl H H H CN H Me COMe H 68 Morpholin-4-yl H H H H H Me COMe H 69 H H H H CO₂Me H Et COMe H 70 H H H H H H Phenyl COMe H 71 H H H H CN H Me COMe H 72 SMe H H H H H Me COMe H 73 SO₂Me H H H H H Me COMe H 74 I H H H H H Me COMe H 75 Br H H H H H Me COMe H

TABLE II Compound R^(1a) R^(1b) R^(1c) R^(1d) R^(2a) R^(2b) R^(2c) R^(2d) R³ R⁴ R⁹ 1 H H H H H H H H Me COMe H 2 H OMe H H H H OMe H Me COMe COMe 3 H H H H H H H H Me COMe COMe 4 H Cl H H H H Cl H Me COMe COMe 5 Me H Me H H Me H Me Me COMe COMe 6 H iso-Pr H H H H iso-Pr H Me COMe COMe 7 H I H H H H I H Me COMe COMe 8 H F H H H H F H Me COMe COMe 9 H Br H H H H Br H Me COMe COMe 10 H Me H H H H Me H Me COMe COMe 11 H Et H H H H Et H Me COMe COMe 12 H Cyclohexyl H H H H Cyclohexyl H Me COMe COMe 13 H n-Bu H H H H n-Bu H Me COMe COMe 14 H SMe H H H H SMe H Me COMe COMe 15 H Me H H H H Me H Me COPh H 16 H Me H H H H Me H Me COEt H 17 H N₃ H H H H N₃ H Me COMe COMe 18 H CO₂Me H H H H CO₂Me H Me COMe H 19 H COMe H H H H COMe H Me COMe COMe 20 H N₃ H H H H N₃ H Me COMe H 21 H H H H Cl H H H Me COMe H 22 H H H H H Cl H H Me COMe H 23 H H H H H H Cl H Me COMe H 24 H H H H H H Br H Me COMe H 25 H H H H H H I H Me COMe H 26 H H H H OMe H H H Me COMe H 27 H H H H H H OMe H Me COMe H 28 H H H H H Me H H Me COMe H 29 H H H H H H Me H Me COMe H 30 H H H H Cl H Me H Me COMe H 31 H H H H Me H Cl H Me COMe H 32 H H H H Cl Cl H H Me COMe H 33 H H H H Cl H Cl H Me COMe H 34 H H H H Cl H H Cl Me COMe H 35 H H H H H Cl Cl H Me COMe H 36 H H H H H Cl H Cl Me COMe H 37 H H H H H H Cyclohexyl H Me COMe H 38 H H H H H H CN H Me COMe H 39 H H H H H Methylenedioxy H Me COMe H 40 H Cl H H H H Me H Me COMe H 41 H Cl H H H H Morpholin-4-yl H Me COMe H 42 H Me H H H H OMe H Me COMe H 43 H Cl H H H H OMe H Me COMe H 44 H H H H H H CO₂Me H Et COMe H 45 H H H H H H CN H Et COMe H 46 H CO₂CHMe₂ H H H H CO₂CHMe₂ H Me COMe H 47 H OMe H H H H Benzoyl H Me COMe H 48 H Cl H H H H CO₂Me H Me COMe H 49 H OMe H H H H CONH₂ H Me COMe H 50 H OMe H H H H CN H Me COMe H 51 H OMe H H H H CO₂Me H Me COMe H 52 H H H Me H H CN H Me COMe H 53 H OMe H H H H Morpholin-4-yl H Me COMe H 54 H Cl H H CONH₂ H H H Me COMe H 55 H Cl H H H H CONH₂ H Me COMe H 56 H H H H H H CONH₂ H Me COMe H 57 H Me H H H H CN H Me COMe H 58 H Me H H H H Morpholin-4-yl H Me COMe H 59 H H H H CONH₂ H H H Me COMe H 60 H H H H H H NHCOMe H Me COMe H 61 H H H H H H CO₂Me H Me COMe H 62 H OMe H H H H NHCOMe H Me COMe H 63 H Morpholin-4-yl H H H H CN H Me COMe H 64 H Morpholin-4-yl H H H H H H Me COMe H 65 H SMe H H H H H H Me COMe H

TABLE III Compound No. R^(1b) X R² 1 H NH Pyrazin-2-yl 2 Cl NH Pyrazin-2-yl 3 H NH Pyridin-4-yl 4 CH₃ S Phenyl 5 H CH₂ Phenyl

According to the invention there is further provided a process for the preparation of a compound of formula (I) which comprises reacting a compound of formula (II):

with a suitable acid anhydride in the presence of a suitable base (such as pyridine) at a suitable temperature (such as room temperature). A compound of formula (II), wherein W and Y are both hydrogen, Z is at the 6-position, R² is para-substituted phenyl where its substituent is the same as Z, and R³ is methyl, can be prepared by a Doebner-von Miller type reaction, that is by reacting an aniline of formula (III):

wherein R is Z or the substituent on R², with acetaldehyde in a suitable solvent (for example ethanol/water) at a suitable temperature (such as room temperature).

Alternatively, a compound of formula (I) can be prepared by reacting a compound of formula (IV):

with a compound of formula (V):

wherein R′ is alkyl, in a suitable solvent (such as acetonitrile) with a suitable base and at a suitable temperature (such as reflux). A compound of formula (IV) can be prepared by chlorinating a compound of formula (VI):

with a suitable chlorinating reagent (such as thionyl chloride) in a suitable solvent (such as dichloromethane). A compound of formula (VI) can be prepared by acylating a compound of formula (VII):

(for example with an acid anhydride (R⁴)₂O) in a suitable solvent (such as dichloromethane). A compound of formula (VII) can be prepared by reacting an aniline of formula (VIII):

with a compound of formula (IX):

in the presence of a suitable acid and solvent (such as aqueous 5% hydrochloric acid).

Alternatively, a compound of formula (VI) can be prepared by acetylation (for example with an acid anhydride (R⁴)₂O) and subsequent reduction of a compound of is formula (X):

Alternatively compounds of formula (I) can be prepared as shown in Scheme 1 below. Both racemic and enantioselective synthesis can be prepared by this route.

Compounds of formula (Ib) can be prepared as shown in Scheme 2 below.

Compounds of formulae (III) and (IX) are commercially available or can be prepared using or adapting literature methods.

In another aspect the present invention provides processes for the preparation of a compound of formula (I), (Ia), (Ib), (Ic), (Id) or (Ie).

Compounds of the invention are useful because they demonstrate pharmacological activity. In particular they demonstrate activity as modulators of the STAT6 signal pathway. The compounds of the invention, being modulators of the STAT6 pathway, can be used to treat atopic dermatitis, urticaria, allergic asthma, allergic rhinitis, food allergies, allergic conjunctivitis, hayfever, bullous pemphigoid, industrial sensitisation or chronic rejection of transplants, or COPD.

The present invention also provides a compound of formula (I):

wherein:

-   L is CH₂, O or S; -   n is 0 or 1; -   W, Y and Z are, independently hydrogen, cyano, nitro, halogen, N₃,     C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆     alkylthio, C₃₋₆ cycloalkyl, CO₂H, CO₂(C₁₋₆ alkyl), CONR⁵R⁶, COR¹⁰,     SO₂R¹², methylenedioxy, NHCOR¹¹ or heterocyclyl; -   R² is aryl or heteroaryl optionally substituted by cyano, nitro,     halogen, N₃, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆     haloalkoxy, C₁₋₆ alkylthio, C₃₋₆ cycloalkyl, CO₂H, CO₂(C₁₋₆ alkyl),     CONR¹³R¹⁴, COR¹⁵, SO₂R¹⁶, methylenedioxy, NHCOR¹⁷ or heterocyclyl; -   R³ is C₁₋₄ alkyl or C₁₋₄, haloalkyl; -   R⁴ is CO(C₁₋₄ alkyl) or CO(C₁₋₄ haloalkyl); -   X is O, S, SO, SO₂, CR⁷R⁸ or NR⁹; -   R⁵, R⁶, R⁷, R⁸, R¹³ and R¹⁴ are, independently, hydrogen or C₁₋₆     alkyl; -   R⁹ is hydrogen, C₁₋₆ alkyl or CO(C₁₋₄ alkyl); -   R¹⁰, R¹¹, R¹², R¹⁵, R¹⁶ and R¹⁷ are, independently, C₁₋₆ alkyl or     phenyl; -   or a pharmaceutically acceptable salt thereof; or a solvate thereof,     for use in medical therapy. The term ‘medical therapy’ as used     herein is intended to include prophylactic, diagnostic and     therapeutic regimens carried out in vivo or ex vivo on humans or     other mammals.

According to the invention there is further provided the use of a compound of invention of formula (I) as defined anywhere above, (Ia), (Ib), (Ic), (Id) or (Ie), or a pharmaceutically acceptable salt thereof; or solvate thereof, in the manufacture of a medicament for use in therapy (such as in the modulation of the STAT6 signal pathway; for example in the treatment of atopic dermatitis, urticaria, allergic asthma, allergic rhinitis, a food allergy, allergic conjunctivitis, hayfever, bullous pemphigoid, industrial sensitization, chronic rejection of transplants or COPD; especially allergic asthma, or allergic rhinitis, or COPD) in a mammal (such as a human).

A method of treating STAT6 mediated disease state {such as atopic dermatitis, urticaria, allergic asthma, allergic rhinitis, a food allergy, allergic conjunctivitis, hayfever, bullous pemphigoid, industrial sensitization, chronic rejection of transplants or COPD; especially allergic asthma, or allergic rhinitis, or COPD} in a mammal (such as a human) which comprises administering to a mammal in need of such treatment an effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id) or (Ie), or a pharmaceutically acceptable salt thereof; or a solvate thereof.

The dose of the compound to be administered will depend on the relevant indication, the age, weight and sex of the patient and may be determined by a physician. The dosage will preferably be in the range of from 0.01 mg/kg to 10 mg/kg.

The compounds may be administered topically, e.g. to the lung and/or the airways, in the form of solutions, suspensions, HFA aerosols or dry powder formulations, for example formulations in the inhaler device known as the TURBUHALER®; or systemically, for example by oral administration in the form of a tablet, pill, capsule, syrup, powder or granule, or by parenteral administration, for example, in the form of sterile parenteral solution or suspension, or by rectal administration, for example in the form of suppositories.

The compounds of the invention may be administered on their own or as a pharmaceutical comprising the compound of the invention in combination with a pharmaceutically acceptable diluent, adjuvant and/or carrier. Particularly preferred are compositions not containing material capable of causing an adverse, such as an allergic, reaction. Also provided by the present invention is a pharmaceutical composition comprising a compound according to the present invention, as active ingredient, together with a pharmaceutically acceptable adjuvant, diluent or carrier.

Dry powder formulations and pressurized HFA aerosols of the compounds of the invention may be administered by oral or nasal inhalation. For inhalation the compound is desirably finely divided. The finely divided compound preferably has a mass median diameter of less than 10 μm, and may be suspended in a propellant mixture with the assistance of a dispersant, such as a C₈–C₂₀ fatty acid or salt thereof, (such as oleic acid), a bile salt, a phospholipid, an alkyl saccharide, a perfluorinated or polyethoxylated surfactant, or other pharmaceutically acceptable dispersant.

The compounds of the invention may also be administered by means of a dry powder inhaler. The inhaler may be a single or a multi dose inhaler, and may be a breath actuated dry powder inhaler.

One possibility is to mix the finely divided compound with a carrier substance, for example a mono-, di- or polysaccharide, a sugar alcohol, or another polyol. Suitable carriers are sugars, for example lactose, glucose, raffinose, melezitose, lactitol, maltitol, trehalose, sucrose or mannitol; and starch. Alternatively the finely divided compound may be coated by another substance. The powder mixture may also be dispensed into hard gelatin capsules, each containing the desired dose of the active compound.

Another possibility is to process the finely divided powder into spheres which break up during the inhalation procedure. This spheronized powder may be filled into the drug reservoir of a multidose inhaler, for example that known as the TURBUHALER® in which a dosing unit meters the desired dose which is then inhaled by the patient. With this system the active compound, with or without a carrier substance, is delivered to the patient.

For oral administration the active compound may be admixed with an adjuvant or a carrier, for example lactose, saccharose, sorbitol or mannitol; a starch, for example potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example gelatin or polyvinylpyrrolidone, and/or a lubricant, for example magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, or the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain for example gum arabic, gelatin, talcum, titanium dioxide, and the like. Alternatively, the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.

For the preparation of soft gelatin capsules, the compound may be admixed with for example a vegetable oil or polyethylene glycol. Hard gelatin capsules may contain granules of the compound using either the above mentioned excipients for tablets. Also liquid or semisolid formulations of the drug may be filled into hard gelatin capsules.

Liquid preparations for oral application may be in the form of syrups or suspensions, for example solutions containing the compound, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain coloring agents, flavoring agents, saccharine and/or carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.

The compounds of the invention may be administered in conjunction with other compounds used for the treatment of the above conditions.

The following Examples illustrate the invention. Throughout the Examples all reactions were performed in dried glassware in an argon or nitrogen atmosphere at room temperature, unless otherwise noted. All solvents and reagents were used as received.

¹H-NMR spectra were recorded at 400 MHz. The residual solvent peak, usually chloroform (δ_(H) 7.27 ppm) was used as internal shift reference. Analytical HPLC was run on a Hewlett Packard LC-MS 1100, using a C-18 reversed phase column and eluting with the following general system: acetonitrile:0.1M NH₄OAc (20:80 to 90:10 gradient)

Preparative LC was run on a Kromasil KR-100-10-C18 column (250×20 mm), using different proportions of acetonitrile:water containing 2.0% HOAc or acetonitrile:0.1M NH₄OAc, as eluent. Chiral separations was performed on Chiralpak AD columns using different proportions of hexane, 2-propanol, methanol and diethylamine. Flash chromatography was performed on silica (Merck 40–63 μm) with the eluents indicated in the specific Examples.

EXAMPLE 1

This Example illustrates the preparation of cis-1-Acetyl-6-ethyl-N-(4-ethylphenyl)-1,2,3,4-tetrahydro-2-methyl-4-quinolinamine (Compound No. 10 Table I)

Step 1: cis-6-Ethyl-N-(4-ethylphenyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinamine

Acetaldehyde (0.77 g, 17.4 mmol) was added to an ice-cooled solution of p-ethylaniline (0.71 g, 5.8 mmol) in aqueous ethanol (20 ml, 60%). After stirring at room temperature for 24 hours the solvents were evaporated. The crude product was purified on silica (ethyl acetate:heptane 1:4) and preparative HPLC to yield the cis:trans isomers in a 1:2 ratio to provide the sub-titled product (0.65 mmol). (The corresponding trans-isomer was also isolated 1.3 mmol.)

Step 2: cis-1-Acetyl-6-ethyl-N-(4-ethylphenyl)- 1,2,3,4-tetrahydro-2-methyl-4-quinolinamine.

The compound of Step 1 (59 mg, 0.20 mmol) was dissolved in pyridine (1 ml) and acetic anhydride (2.0 mmol) was added. After stirring at room temperature for 20 hours the solvent was evaporated and the crude product was purified on silica (ethyl acetate:heptane 1:2). The title compound was obtained as a colorless oil (0.12 mmol).

¹H NMR CDCl₃: δ 7.23 (1H, s); 7.16–7.00 (4H, m); 6.63 (2H, d); 4.90 (1H, br s); 4.24–4.14 (1H, m); 3.82–3.68 (1H, m); 2.70–2.52 (5H, m); 2.20 (3H, s); 1.38–1.15 (10H, m).

EXAMPLE 2

This Example illustrates the preparation of 4-{[(2S*,4R*)-1-acetyl-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]amino}benzonitrile (Compound No. 36 of Table I) and the preparation of 4-[{(2R*,4R*)1-acetyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl}amino]-benzonitrile. (Compound No. 45 Table II).

Step 1: 1-(4-Hydroxy-2-methyl-3,4-dihydro-2H-quinolin-1-yl)-ethanone.

A solution of 1,2,3,4-tetrahydro-2-methyl-4-quinolinol (5.9 g, 36.4 mmol) and acetic anhydride (37.1 g, 364 mmol) in dichloromethane (100 ml) was stirred for one hour. The solvents were evaporated and the crude product was purified on silica (ethyl acetate:heptane 1:1) to obtain the sub-titled product (33.5 mmol).

Step 2:

1-(4-Hydroxy-2-methyl-3,4-dihydro-2H-quinolin-1-yl)-ethanone (3.1 g, 15 mmol) was dissolved in dry dichloromethane (50 ml). Thionyl chloride (1.96 g, 16.5 mmol) was added at −10° C. and the reaction mixture was stirred vigorously for about 30 minutes. The reaction mixture was filtered through a short plug of silica and eluted with dichloromethane. The solvents were removed by reduced pressure affording a yellowish oil (2.15 g).

The oil was dissolved in dry acetonitrile (60 ml) and 4-aminobensonitrile (3.54 g, 30 mmol) was added. The flask was sealed and heated at 80° C. for 12 h. The solvent was removed at reduced pressure and the crude product was purified on silica using ethyl acetate:heptane 1:1 as eluent, affording the product (4.6 mmol). The product was further purified on preparative HPLC to yield the cis/trans diastereomers in a 2:3 ratio (1.8 mmol of the cis compound and 2.7 mmol of the trans compound) as white solids after lyophilisation. The enantiomers were resolved according to the general procedures.

Compound No. 36 of Table I: [α]_(D) ²⁰=171° (c=0.28, CH₂Cl₂); ¹H NMR CDCl₃: δ 7.46 (2H, d); 7.32 (1H, dt); 7.24–7.14 (3H, m); 6.63 (2H, d); 5.00–4.88 (1H, m); 4.42 (1H, br d); 4.31–4.23 (1H, m); 2.73–2.63 (1H, m); 2.20 (3H, s); 1.34 (1H, q); 1.17 (3H, d).

Compound No. 45 Table II: [α]_(D) ²⁰=56° (c=0.53, CH₂Cl₂); ¹H NMR CDCl₃: δ 7.45–7.18 (6H, m); 6.62 (2H, d); 5.0–4.85 (1H, m); 4.62 (1H, t); 4.40 (1H, d); 2.58–2.49 (1H, m); 2.18 (3H, s); 1.82–1.75 (1H, m); 1.20 (3H, d).

EXAMPLE 3

This Example illustrates the preparation of (2S,4R)-1-Acetyl-2-methyl-N-phenyl-1,2,3,4-tetrahydro-4-quinolinamine (Compound No. 1 of Table I).

Step 1: 1-[(2S)-2-methyl-4-(phenylimino)-3,4-dihydro-1(2H)-quinolinyl]-1-ethanone.

A solution of (2S)-1-acetyl-2-methyl-2,3-dihydro-4(1H)-quinolinone (20 mg, 0.098 mmol; preparation see Tetrahedron: Asymmetry (1998), 9(7), 1137–1142), aniline (36 μl, 0.394 mmol) and a catalytic amount of p-toluene sulfonic acid monohydrate was refluxed overnight in toluene (4 ml) containing molcular sieve 3 Å (0.9 g). The resulting mixture was filtered, concentrated and purified on silica (ethyl acetate:heptane 1:2) to obtain the sub-titled product (22.8 mg, 0.082 mmol).

Step 2: (2S, 4R)-1-Acetyl-2-methyl-N-phenyl-1,2,3,4-tetrahydro-4-quinolinamine.

A solution of the product of Step 2 (13 mg, 0.047 mmol) in ethyl acetate (5 ml) was hydrogenated for four hours at 1 atmosphere in the presence of palladium on charcoal (15 mg, 10%). The mixture was filtered and the residue was concentrated and purified on silica (ethyl acetate:heptane 1:2). The title compound was obtained as a colorless oil (0.025 mmol). [α]_(D) ²⁰=236° (c0.53, CH₂Cl₂).

¹H NMR CDCl₃: δ 7.37–7.11 (6H, m); 6.77 (1H, t); 6.66 (2H, d); 4.92 (1H, br d); 4.22 (1H, dd); 4.14–3.60 (1H, br s); 2.70–2.61 (1H, m); 2.18 (3H, s); 1.35–1.22 (1H, m); 1.17 (3H, d).

EXAMPLE 4

This Example illustrates the preparation of cis-1-acetyl-2,6-dimethyl-1,2,3,4-tetrahydro-4-quinolinyl phenyl sulfide (Compound No. 4 of Table III).

To a mixture of 1-acetyl-4-chloro-1,2,3,4-tetrahydro-2,6-dimethyl-quinoline (200 mg, 0.84 mmol) and sodium hydride (20 mg) in THF (2 ml) was added a solution of benzenethiol (66 μl, 1.2 mmol) in THF (1 ml). The mixture was stirred for 16 hrs. Water was added and the product was extracted with ethyl acetate. The crude product was purified on silica (ethyl acetate/heptane) and with preparative HPLC to yield the sub-title product (0.18 mmol) together with its trans isomer (0.12 mmol).

¹H NMR CDCl₃: δ 7.42–7.40 (6H, m); 7.21 (1H, d); 7.04–6.95 (1H, d); 4.81 (1H, s); 4.03 (1H, dd); 2.62 (1H, m); 2.39 (3H, s); 2.16 (3H, s); 1.41–1.32 (1H, m); 1.12 (3H, d).

EXAMPLE 5

This Example illustrates the preparation of cis-1-Acetyl-2-methyl-4-(phenylmethyl)-1,2,3,4-tetrahydroquinoline (Compound No. 5 of Table III).

To a solution of (2S)-1-acetyl-2-methyl-2,3-dihydro-4(1H)-quinolinone (100 mg, 0.49 mmol) in dry toluene (5 ml) was added benzyl magnesium chloride (0.98 mmol, 1.3M in THF). The solution was refluxed for 5 hrs and then quenched with aqueous sulfuric acid. The aqueous phase was extracted with ether, the solvents were evaporated and the crude product was purified on silica (ethyl acetate/heptane) to obtain a yellow oil (79 mg). The oil was dissolved in THF (3 ml) and aqueous sulfuric (2M, 10 ml) acid was added. The solution was stirred over night, extracted with ether and the solvents were evaporated to a yellow oil (40 mg). The crude product was dissolved in ethyl acetate (10 mg) and was hydrogenated for 16 hours at 1 atmosphere in the presence of palladium on charcoal (100 mg, 10%). The mixture was filtered and the residue was concentrated and purified with preparative HPLC. The title compound was obtained as colorless oil (16 mg, 0.20 mmol).

¹H NMR CDCl₃: δ 7.39–7.21 (8H, m); 7.17 (1H, br d); 4.87 (1H, br s); 3.48 (1H, dd); 2.79–2.65 (1H, m); 3.62 (1H, dd); 2.29–2.22 (1H, m); 2.17 (3H, s); 1.02 (3H, d); 0.90–0.81 (1H, m).

Proton NMR data are provided for compounds of formula (I).

cis-1-Acetyl-1,2,3,4-tetrahydro-6-methoxy-N-(4-methoxyphenyl)-2-methyl-4-quinolinamine (Compound No. 2 Table I).

¹H NMR CDCl₃: δ 7.03 (1H, br d); 6.92 (1H, d); 6.78 (3H, m); 6.61 (2H, m); 4.90 (1H, br s); 4.09 (1H, br d); 3.76 (3H, s); 3.73 (3H, s); 3.50 (1H, br s); 2.66–2.57 (1H, m); 2.14 (3H, s); 1.22–1.05 (4H, m).

cis-1-Acetyl-6-chloro-N-(4-chlorophenyl)-1,2,3,4-tetrahydro-2-methyl-4-quinolinamine (Compound No. 3 Table I).

¹H NMR CDCl₃: δ 7.29–7.21 (1H, m); 7.19–7.03 (4H, m); 6.54 (2H, d); 4.86 (1H, br s); 4.14–4.06 (1H, m); 3.85 (1H, d); 2.67–2.59 (1H, m); 2.17 (3H, s); 1.32–1.19 (1H, m); 1.14 (3H, d).

cis-1-Acetyl-1,2,3,4-tetrahydro-2-methyl-6-(1-methylethyl)-N-[4-(1-methylethyl)phenyl]-4-quinolinamine (Compound No. 4 Table I).

¹H NMR CDCl₃: δ 7.24 (1H, br s); 7.16–7.03 (4H, m); 6.64 (2H, d); 4.88 (1H, br d); 4.20 (1H, br d); 3.68 (1H, br s); 2.96–2.78 (2H, m); 2.70–2.60 (1H, m); 2.19 (3H, s); 1.33–1.18 (13H, m); 1.16 (3H, d).

cis-1-Acetyl-1,2,3,4-tetrahydro-6-iodo-N-(4-iodophenyl)-2-methyl-4-quinolinamine (Compound No. 5 Table I).

¹H NMR CDCl₃: δ 7.64 (1H, dd); 7.58 (1H, s); 7.46 (2H, d); 6.91 (1H, br d); 6.42 (2H, d); 4.86 (1H, br d); 4.16–4.07 (1H, m); 3.80 (1H, d); 2.68–2.58 (1H, m); 2.18 (3H, s); 1.35–1.20 (1H, m); 1.16(3H, d).

(2S*,4R*)-1-Acetyl-6-bromo-N-(4-bromophenyl)-1,2,3,4-tetrahydro-2-methyl-4-quinolinamine (Compound No. 6 Table I). [α]_(D) ²⁰=267° (c=0.004, CH₂Cl₂).

¹H NMR CDCl₃: δ 7.44–7.36 (2H, m); 7.27 (2H, d); 7.02 (1H, br d); 6.49 (2H, d); 4.85 (1H, br s); 4.15–4.05 (1H, m); 3.87 (1H, d); 2.67–2.58 (1H, m); 2.17 (3H, s); 1.34–1.18 (1H, m); 1.14(3H, d).

cis-1-Acetyl-6-fluoro-N-(4-fluorophenyl)-1,2,3,4-tetrahydro-2-methyl-4-quinolinamine (Compound No. 7 Table I).

¹H NMR CDCl₃: δ 7.16–6.86 (5H, m); 6.60–6.53 (2H, m); 4.91 (1H, br s); 4.14–4.04 (1H, m), 3.75 (1H, d); 2.70–2.60 (1H, m); 2.17 (3H, s); 1.34–1.18 (1H, m); 1.14 (3H, d).

(2S*,4R*)-1-Acetyl-1,2,3,4-tetrahydro-2,6-dimethyl-N-(4-methylphenyl)-4-quinolinamine (Compound No. 9 Table I). [α]_(D) ²⁰=36° (c=0.28, CH₂Cl₂).

¹H NMR CDCl₃: δ 7.17 (1H, s); 7.12–6.98 (4H, m); 6.58 (2H, d); 4.89 (1H, br s); 4.15 (1H, br d); 3.66 (1H, br s); 2.68–2.58 (1H, m); 2.32 (3H, s); 2.27 (3H, s); 2.18 (3H, s); 1.36–1.18 (1H, m); 1.14 (3H, d).

cis-1-Acetyl-6-cyclohexyl-N-(4-clohexylphenyl)-1,2,3,4-tetrahydro-2-methyl-4-quinolinamine (Compound No. 11 Table I).

¹H NMR CDCl₃: δ 7.21 (1H, s); 7.12–6.98 (4H, m); 6.61 (2H, d); 4.85 (1H, br s); 4.22–4.11 (1H, m); 3.62 (1H, d); 2.68–2.57 (1H, m); 2.54–2.34 (2H, m); 2.17 (3H, s); 1.94–1.12 (24H, m).

cis-1-Acetyl-6-butyl-N-(4-butylphenyl)-1,2,3,4-tetrahydro-2-methyl-4-quinolinamine (Compound No. 12 Table I).

¹H NMR CDCl₃: δ 7.18 (1H, s); 7.12–6.97 (4H, m); 6.61 (2H, d); 4.88 (1H, br s); 4.22–4.12 (1H, m); 3.68 (1H, br d); 2.70–2.46 (5H, m); 2.18 (3H, s); 1.66–1.49 (4H, m); 1.44–1.12 (8H, m); 1.02–0.86 (6H, m).

cis-1-Acetyl-1,2,3,4-tetrahydro-2-methyl-6-(methylthio)-N-[4-(methylthio)phenyl]-4-quinolinamine (Compound No. 13 Table I).

¹H NMR CDCl₃: δ 7.23–6.98 (5H, m); 7.57 (2H, d); 4.92–4.74 (1H, m); 4.18–4.10 (1H, m); 3.84 (1H, br d); 2.66–2.57 (1H, m); 2.40 (3H, s); 2.38 (3H, s); 2.15 (3H, s); 1.32–1.18 (1H, m); 1.13 (3H, d).

cis-1,2,3,4-Tetrahydro-2,6-dimethyl-N-(4-methylphenyl)-1-(1-oxopropyl)-4-quinolinamine (Compound No. 15 Table I).

¹H NMR CDCl₃: δ 7.14 (1H, s); 7.09–6.97 (4H, m); 6.56 (2H, d); 4.96–4.82 (1H, m); 4.11 (1H, dd); 3.64 (1H, br s); 2.66–2.32 (3H, m); 2.31 (3H, s); 2.25 (3H, s); 1.34–1.08 (7H, m).

cis-1-Acetyl-6-azido-N-(4-azidophenyl)-1,2,3,4-tetrahydro-2-methyl-4-quinolinamine (Compound No. 16 Table I).

¹H NMR CDCl₃: δ 7.18–6.82 (5H, m); 6.61 (2H, d); 4.88 (1H, br s); 4.13 (1H, dd); 3.77 (1H, br s); 2.68–2.60 (1H, m); 2.16 (3H, s); 1.34–1.10 (4H, m).

cis-1-Acetyl-4-[(4-carboxyphenyl)amino]-1,2,3,4-tetrahydro-2-methyl-6-quinolinecarboxylic acid (Compound No. 17 Table I).

¹H NMR MeOD (two protons are obscured by the H₂O-signal): δ 7.96–7.74 (4H, m); 7.33 (1H, d); 6.68 (2H, d); 4.37 (1H, dd); 2.74–2.62 (1H, m); 2.24–2.13 (3H, m); 1.43–1.23 (1H, m); 1.17 (3H, d).

cis-1-Acetyl-1,2,3,4-tetrahydro-4-[[4-(methoxycarbonyl)phenyl]amino]-2-methyl-6-quinolinecarboxylic acid methyl ester (Compound No. 18 Table I).

¹H NMR CDCl₃: δ 7.99 (1H, dd); 7.94–7.86 (3H, m); 7.28–7.20 (1H, m); 6.62 (2H, d); 4.94–4.82 (1H, m); 4.37–4.23 (2H, m); 3.85 (6H, s); 2.74–2.64 (1H, m); 2.22 (3H, s); 1.40–1.28 (1H, m); 1.18 (3H, d).

cis-1-Acetyl-N-(2-chlorophenyl)-1,2,3,4-tetrahydro-2-methyl-4-quinolinamine (Compound No. 19 Table I).

¹H NMR CDCl₃: δ 7.36–7.08 (6H, m); 6.70 (1H, dt); 6.61 (1H, d); 4.95 (1H, br d); 4.51 (1H, d); 4.31–4.22 (1H, m); 2.76–2.66 (1H, m); 2.20 (3H, s); 1.38 (1H, q); 1.19 (3H, d).

cis-1-Acetyl-N-(3chlorophenyl)-1,2,3,4-tetrahydro-2-methyl-4-quinolinamine (Compound No. 20 Table I).

¹H NMR CDCl₃: δ 7.34–7.07 (5H, m); 6.76–6.70 (1H, m); 6.63 (1H, t); 6.52 (1H, dd); 5.00–4.85 (1H, m); 4.25–4.16 (1H, m); 3.91 (1H, d); 2.71–2.61 (1H, m); 2.20 (3H, s); 1.35–1.22 (1H, m); 1.17 (3H, d).

cis-1-Acetyl-N-(4-chlorophenyl)-1,2,3,4-tetrahydro-2-methyl-4-quinolinamine (Compound No. 21 Table I).

¹H NMR CDCl₃: δ 7.35–7.07 (6H, m); 6.61–6.53 (2H, m); 5.00–4.84 (1H, m); 4.17 (1H, d); 3.86 (11H, br s); 2.71–2.60 (1H, m); 2.20 (3H, s); 1.35–1.22 (1H, m);. 1.16 (3H, d).

cis-1-Acetyl-N-(4-bromophenyl)-1,2,3,4-tetrahydro-2-methyl-4-quinolinamine (Compound No. 22 Table I).

¹H NMR CDCl₃: δ 7.34–7.10 (5H, m); 6.89 (1H, br s); 6.53 (2H, d); 5.00–4.85 (1H, m); 4.17 (1H, dd); 2.71–2.60 (1H, m); 2.20 (3H, s); 1.34–1.22 (1H, m); 1.17 (3H, d).

cis-1-Acetyl-1,2,3,4-tetrahydro-N-(4-iodophenyl)-2-methyl-4-quinolinamine (Compound No. 23 Table I).

¹H NMR CDCl₃: δ 7.45 (2H, d); 7.34–7.10 (4H, m); 6.44 (2H, d); 4.99–4.85 (1H, m); 4.17 (1H, dd); 3.88 (1H, br s); 2.70–2.60 (1H, m); 2.19 (3H, s); 1.34–1.21 (1H, m); 1.16 (3H, d).

cis-1-Acetyl-1,2,3,4-tetrahydro-N-(2-methoxyphenyl)-2-methyl-4-quinolinamine (Compound No. 24 Table I).

¹H NMR CDCl₃: δ 7.34–7.25 (2H, m); 7.23–7.10 (2H, m); 6.88–6.81 (2H, m); 6.77–6.70 (1H, m); 6.54 (1H, d); 5.00–4.86 (1H, m); 4.47 (1H, br s); 4.21 (1H, dd); 3.92 (3H, s); 2.73–2.64 (1H, m); 2.20 (3H, s); 1.40–1.28 (1H, m); 1.17 (3H, d).

cis-1-Acetyl-1,2,3,4-tetrahydro-N-(4-methoxyphenyl)-2-methyl-4-quinolinamine (Compound No. 25 Table I).

¹H NMR CDCl₃: δ 7.36–7.09 (4H, m); 6.79 (2H, d); 6.64–6.57 (2H, m); 4.96–4.82 (1H, m); 4.13 (1H, dd); 3.74 (3H, s); 2.68–2.59 (1H, m); 2.17 (3H, s); 1.28–1.10 (4H, m).

cis-1-Acetyl-1,2,3,4-tetrahydro-2-methyl-N-(3-methylphenyl)-4-quinolinamine (Compound No. 26 Table I).

¹H NMR CDCl₃: δ 7.37–7.03 (5H, m); 6.58 (1H, d); 6.51–6.41 (2H, m); 4.96–4.82 (1H, m); 4.21 (1H, dd); 2.69–2.59 (1H, m); 2.27 (3H, s); 2.18 (3H, s); 1.30–1.19 (1H, m); 1.15 (3H, d).

(2S*,4R*)-1-Acetyl-2-methyl-N-(4-methylphenyl)-1,2,3,4-tetrahydro-4-quinolinamine (Compound No. 27 Table I). [α]_(D) ²⁰=183° (c=0.36, CH₂Cl₂);

¹H NMR CDCl₃: δ 7.36–7.08 (4H, m); 7.00 (2H, d); 6.56 (2H, d); 4.96–4.82 (1H, m); 4.17 (1H, dd); 2.68–2.59 (1H, m); 2.24 (3H, s); 2.18 (3H, s); 1.30–1.10 (4H, m).

cis-1-Acetyl-N-(2-chloro-4-methylphenyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinamine (Compound No. 28 Table I).

¹H NMR CDCl₃: δ 7.32–7.08 (5H, m); 6.90 (1H, dd); 6.50 (1H, d); 4.91 (1H, br d); 4.33 (1H, br s); 4.21 (1H, dd); 2.73–2.63 (1H, m); 2.23 (3H, s); 2.18 (3H, s); 1.40–1.27 (1H, m); 1.16(3H, d).

cis-1-Acetyl-N-(4-chloro-2-methylphenyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinamine (Compound No. 29 Table I).

¹H NMR CDCl₃: δ 7.32–6.98 (6H, m); 6.41 (1H, d); 4.92 (1H, br d); 4.25–4.15 (1H, m); 3.63 (1H, br d); 2.72–2.62 (1H, m); 2.21 (3H, s); 2.18 (3H, s); 1.39–1.27 (1H, m); 1.16 (3H, d).

cis-1-Acetyl-N-(2,3-dichlorophenyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinamine (Compound No. 30 Table I).

¹H NMR CDCl₃: δ 7.33–7.12 (4H, m); 7.02 (1H, t); 6.84 (1H, dd); 6.48 (1H, d); 4.93 (1H, br s); 4.64 (1H, br d); 4.28–4.20 (1H, m); 2.74–2.65 (1H, m); 2.18 (3H, s); 1.44–1.31 (1H, m); 1.16(3H, d).

cis-1-Acetyl-N-(2,4-dichlorophenyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinamine (Compound No. 31 Table I).

¹H NMR CDCl₃: δ 7.34–7.10 (5H, m); 7.06 (1H, dd); 6.50 (1H, d); 4.92 (1H, br s); 4.46 (1H, br d); 4.24–4.16 (1H, m); 2.73–2.64 (1H, m); 2.18 (3H, s); 1.36 (1H, q); 1.16 (3H, d).

cis-1-Acetyl-N-(2,5-dichlorophenyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinamine (Compound No. 32 Table I).

¹H NMR CDCl₃: δ 7.34–7.12 (5H, m); 6.65 (1H, dd); 6.55 (1H, d); 4.98–4.86 (1H, m); 4.53 (1H, br d); 4.26–4.17 (1H, m); 2.74–2.64 (1H, m); 2.21 (3H, s); 1.36 (1H, q); 1.17 (3H, d).

cis-1-Acetyl-N-(3,4-dichlorophenyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinamine (Compound No. 33 Table I).

¹H NMR CDCl₃: δ 7.33–7.10 (5H, m); 6.70 (1H, d); 6.47 (1H, dd); 4.97–4.84 (1H, m); 4.14 (1H, dd); 2.68–2.58 (1H, m); 2.18 (3H, s); 1.32–1.20 (1H, m); 1.15 (3H, d).

cis-1-Acetyl-N-(3,5-dichlorophenyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinamine (Compound No. 34 Table I).

¹H NMR CDCl₃: δ 7.34–7.11 (4H, m); 6.72 (1H, t); 6.49 (2H, d); 4.96–4.84 (1H, m); 4.21–4.12 (1H, m); 4.06–3.96 (1H, m); 2.68–2.58 (1H, m); 2.20 (3H, s); 1.33–1.20 (1H, m); 1.15 (3H, d).

cis-1-Acetyl-N-(4-cyclohexylphenyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinamine (Compound No. 35 Table I).

¹H NMR CDCl₃: δ 7.36 (1H, d); 7.30–7.08 (3H, m); 7.03 (2H, d); 6.59 (2H, d); 4.94–4.81 (1H, m); 4.17 (1H, dd); 3.76 (1H, br s); 2.68–2.58 (1H, m); 2.44–2.34 (1H, m); 2.17 (3H, s); 1.90–1.18 (11H, m); 1.14 (3H, d).

cis-1-Acetyl-N-(1,3-benzodioxol-5-yl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinamine (Compound No. 37 Table I).

¹H NMR CDCl₃: δ 7.37–7.08 (4H, m); 6.65 (1H, d); 6.28 (1H, d); 6.08 (1H, dd); 5.87 (2H, s); 4.89 (1H, br d); 4.30–3.98 (2H, m); 2.68–2.57 (1H, m); 2.18 (3H, s); 1.22 (1H, q); 1.14 (3H, d).

cis-1-Acetyl-6-chloro-2-methyl-N-(4-methylphenyl)-1,2,3,4-tetrahydro-4-quinolinamine (Compound No. 38 Table I).

¹H NMR CDCl₃: δ 7.34 (1H, s); 7.27–7.22 (1H, m); 7.10–6.97 (3H, m); 6.55 (2H, d); 4.85 (1H, br s); 4.12 (1H, dd); 2.68–2.58 (1H, m); 2.25 (3H, s); 2.16 (3H, s); 1.30–1.18 (1H, m); 1.14 (3H, d).

cis-1-Acetyl-6-chloro-2-methyl-N-[4-(4-morpholinyl)phenyl]-1,2,3,4-tetrahydro-4-quinolinamine (Compound No. 39 Table I).

¹H NMR CDCl₃: δ 7.28 (1H, s); 7.22–7.16 (1H, m); 7.06–6.96 (1H, m); 6.86–6.73 (2H, m); 6.55 (2H, br d); 4.79 (1H, br s); 4.03 (1H, br d); 3.80 (4H, br s); 2.98 (4H, br s); 2.62–2.52 (1H, m); 2.10 (3H, s); 1.24–1.03 (4H, m).

cis-1-Acetyl-N-(4-methoxyphenyl)-2,6-dimethyl-1,2,3,4-tetrahydro-4-quinolinamine (Compound No. 40 Table I).

¹H NMR CDCl₃: δ 7.17 (1H, s); 7.11–6.98 (2H, m); 6.81 (2H, d); 6.63 (2H, d); 4.88 (1H, br s); 4.11 (1H, dd); 3.77 (3H, s); 3.54 (1H, br s); 2.68–2.58 (1H, m); 2.34 (3H, s); 2.17 (3H, s); 1.27–1.10 (4H, m).

cis-1-Acetyl-6-chloro-N-(4-methoxyphenyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinamine (Compound No. 41 Table I).

¹H NMR CDCl₃: δ 7.34 (1H, d); 7.28–7.22 (1H, m); 7.13–7.01 (1H, m); 6.80 (2H, d); 6.59 (2H, d); 4.84 (1H, br s); 4.07 (1H, dd); 3.75 (3H, s); 2.68–2.58 (1H, m); 2.16 (3H, s); 1.28–1.10 (4H, m).

cis-1-Acetyl -4-[[4-(ethoxycarbonyl)phenyl]amino]-1,2,3,4-tetrahydro-2-methyl-6-quinolinecarboxylic acid ethyl ester (Compound No. 42 Table I).

¹H NMR CDCl₃: δ 7.99 (1H, dd); 7.94–7.86 (3H, m); 7.23 (1H, d); 6.62 (2H, d); 4.94–4.82 (1H, m); 4.38–4.25 (5H, m); 2.74–2.64 (1H, m); 2.21 (3H, s); 1:39–1.27 (7H, m); 1.17 (3H, d).

cis-4-{[1-Acetyl-2-ethyl-1,2,3,4-tetrahydro-4-quinolinyl]amino}benzonitrile (Compound No. 43 Table I).

¹H NMR CDCl₃: δ 7.45 (2H, d); 7.31 (1H, dt); 7.23–7.08 (3H, m); 6.60 (2H, d); 4.87 (1H, br s); 4.35 (1H, d); 4.31–4.22 (1H, m); 2.71–2.61 (1H, m); 2.17 (3H, s); 1.64–1.22 (3H, m); 0.86 (3H, t).

cis-1-Acetyl-1,2,3,4-tetrahydro-2-methyl-4-[[4-[(1-methylethoxy)carbonyl]-phenyl]amino]-6-quinolinecarboxylic acid 1-methylethyl ester (Compound No. 44 Table I).

¹H NMR CDCl₃: δ 7.97 (1H, dd); 7.93–7.86 (3H, m); 7.22 (1H, d); 6.63 (2H, d); 5.24–5.12 (2H, m); 4.94–4.83 (1H, m); 4.34 (1H, dd); 2.74–2.65 (1H, m); 2.20 (3H, s); 1.38–1.23 (13H, m); 1.17 (3H, d).

cis-1-Acetyl-N-(4-chlorophenyl)-6-methoxy-2-methyl-1,2,3,4-tetrahydro-4-quinolinamine (Compound No. 45 Table I).

¹H NMR CDCl₃: δ 7.19–7.02 (3H, m); 6.88–6.78 (2H, m); 6.58 (2H, br s); 4.93 (1H, br s); 4.13 (1H, dd); 3.75 (3H, s); 2.68–2.58 (1H, m); 2.16 (3H, s); 1.31–1.18 (1H, m); 1.13 (3H, d).

cis-1-Acetyl-6-methoxy-2-methyl-N-(4-methylphenyl)-1,2,3,4-tetrahydro-4-quinolinamine (Compound No. 46 Table I).

¹H NMR CDCl₃: δ 7.10–6.92 (4H, m); 6.80 (1H, dd); 6.64 (2H, br s); 4.90 (1H, br s); 4.16 (1H, dd); 3.75 (3H, s); 2.68–2.58 (1H, m); 2.26 (3H, s); 2.15 (3H, s); 1.30–1.17 (1H, m); 1.12 (3H, d).

cis-4-{[1-Acetyl-6-methoxy-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]amino}-phenyl)(phenyl)methanone (Compound No. 47 Table I).

¹H NMR CDCl₃: δ 7.80–7.71 (4H, m); 7.57–7.42 (3H, m); 7.09 (1H, br d); 6.86–6.79 (2H, m); 6.66 (2H, d); 4.97 (1H, br s); 4.30 (1H, dd); 3.75 (3H, s); 2.73–2.63 (1H, m); 2.17 (3H, s); 1.38–1.23 (1H, m); 1.16 (3H, d).

cis-4-{[1-Acetyl-6-chloro-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl]amino}benzoic acid methyl ester (Compound No. 48 Table I).

¹H NMR CDCl₃: δ 7.89 (2H, d); 7.30–7.17 (2H, m); 7.10 (1H, br d); 6.59 (2H, d); 4.89 (1H, br s); 4.29–4.18 (2H, m); 3.86 (3H, s); 2.71–2.62 (1H, m); 2.18 (3H, s); 1.38–1.24 (1H, m); 1.15 (3H, d).

cis-1-(4-{[1-Acetyl-6-methoxy-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]amino}-phenyl)ethanone (Compound No. 49 Table I).

¹H NMR CDCl₃: δ 7.86 (2H, d); 7.08 (1H, br d); 6.86–6.75 (2H, m); 6.63 (2H, d); 4.96 (1H, br s); 4.29 (1H, dd); 3.74 (3H, s); 2.71–2.62 (1H, m); 2.52 (3H, s); 2.18 (3H, s); 1.36–1.23 (1H, m); 1.15 (3H, d).

cis-4-{[1-Acetyl-6-methoxy-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]amino}-benzamide (Compound No. 50 Table I).

¹H NMR CDCl₃: δ 7.70 (2H, d); 7.08 (1H, br d); 6.86–6.76 (2H, m); 6.64 (2H, d); 6.18 (2H, br s); 4.96 (1H, br s); 4.26 (1H, dd); 3.74 (3H, s); 2.70–2.61 (1H, m); 2.18 (3H, s); 1.35–1.21 (1H, m); 1.15 (3H, d).

cis-4-{[1-Acetyl-6-methoxy-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]amino}-benzonitrile (Compound No. 51 Table I).

¹H NMR CDCl₃: δ 7.45 (2H, d); 7.14–7.03 (1H, m); 6.81 (1H, dd); 6.71 (1H, d); 6.61 (2H, d); 4.94 (1H, br s); 4.32–4.16 (2H, m); 3.73 (3H, s); 2.68–2.59 (1H, m); 2.16 (3H, s); 1.34–1.22 (1H, m); 1.14 (3H, d).

cis-4-[{1-Acetyl-1,2,3,4-tetrahydro-6-methoxy-2-methyl-4-quinolinyl}amino]-benzoic acid methyl ester (Compound No. 52 Table I).

¹H NMR CDCl₃: δ 7.86 (2H, d); 7.05 (1H, br d); 6.82–6.73 (2H, m); 6.60 (2H, d); 4.93 (1H, br s); 4.40–4.18 (2H, m); 3.84 (3H, s); 3.70 (3H, s); 2.68–2.58 (1H, m); 2.15 (3H, s); 1.32–1.19 (1H, m); 1.13 (3H, d).

cis-4-{[1-Acetyl-2,8-dimethyl-1,2,3,4-tetrahydro-4-quinolinyl]amino}benzonitrile (Compound No. 53 Table I).

¹H NMR CDCl₃: δ 7.44 (2H, d); 7.27–7.12 (2H, m); 7.00 (1H, d); 6.58 (2H, d); 5.23–5.12 (1H, m); 4.33 (1H, br d); 4.19–4.10 (1H, m); 2.72–2.63 (1H, m); 2.27 (3H, s); 1.95 (3H, s); 1.21–1.13 (1H, m); 1.06 (3H, d).

cis-1-Acetyl-6-methoxy-2-methyl-N-[4-(4-morpholinyl)phenyl]-1,2,3,4-tetrahydro-4-quinolinamine (Compound No. 54 Table I).

¹H NMR CDCl₃: δ 7.04 (1H, br d); 6.94–6.76 (4H, m); 6.64 (2H, d); 4.90 (1H, br s); 4.18–4.07 (1H, m); 3.90–3.81 (5H, m); 3.75 (3H, s); 3.10–2.94 (4H, m); 2.68–2.57 (1H, m); 2.15 (3H, s); 1.24–1.08 (4H, m).

cis-2-{[1-Acetyl-6-chloro-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]amino}-benzamide (Compound No. 55 Table I).

¹H NMR CDCl₃: δ 8.24 (1H, d); 7.46 (1H, dd); 7.34–7.20 (3H, m); 7.08 (1H, br s); 6.67 (1H, t); 6.56 (1H, d); 5.84 (2H, br s); 4.88 (1H, br s); 4.23–4.14 (1H, m); 2.73–2.64 (1H, m); 2.18 (3H, s); 1.47–1.33 (1H, m); 1.15 (3H, d).

cis-4-{[1-Acetyl-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]amino}benzamide (Compound No. 56 Table I).

¹H NMR CDCl₃: δ 7.69 (2H, d); 7.34–7.13 (4H, m); 6.64 (2H, d); 5.93 (2H, br s); 4.95 (1H, br d); 4.34–4.22 (2H, m); 2.73–2.64 (1H, m); 2.21 (3H, s); 1.32 (1H, q); 1.18 (3H, d).

cis-4-{[1-Acetyl-2,6-dimethyl-1,2,3,4-tetrahydro-4-quinolinyl]amino}benzonitrile (Compound No. 57 Table I).

¹H NMR CDCl₃: δ 7.47 (2H, d); 7.16–6.93 (3H, m); 6.63 (2H, d); 4.93 (1H, br s); 4.33–4.19 (2H, m); 2.70–2.60 (1H, m); 2.32 (3H, s); 2.18 (3H, s); 1.31 (1H, q); 1.16 (3H, d).

cis-1-Acetyl-1,2,3,4-tetrahydro-2,6-dimethyl-N-[4-(4-morpholinyl)phenyl]-4-quinolinamine (Compound No. 58 Table I).

¹H NMR CDCl₃: δ 7.17 (1H, s); 7.11–6.99 (2H, m); 6.86 (2H, d); 6.64 (2H, d); 4.89 (1H, br s); 4.13 (1H, dd); 3.86 (4H, t); 3.57 (1H, br s); 3.05 (4H, t); 2.68–2.58 (1H, m); 2.32 (3H, s); 2.16 (3H, s); 1.29–1.10 (4H, m).

cis-2-{[1-Acetyl-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]amino}benzamide (Compound No. 59 Table I).

¹H NMR CDCl₃: δ 8.27 (1H, d); 7.44 (1H, d); 7.34–7.06 (4H, m); 6.70–6.59 (2H, m); 5.73 (2H, br s); 4.92 (1H, br s); 4.31–4.21 (1H, m); 2.75–2.65 (1H, m); 2.18 (3H, s); 1.38 (1H, q); 1.15 (3H, d).

cis-N-(4-{[1-Acetyl-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]amino}phenyl)-acetamide (Compound No. 60 Table I).

¹H NMR CDCl₃: δ 7.32–7.08 (5H, m); 7.02–6.90 (1H, br s); 6.59 (2H, d); 4.90 (1H, br d); 4.17 (1H, br d); 3.76 (1H, br s); 2.70–2.59 (1H, m); 2.18 (3H, s); 2.13 (3H, s); 1.32–1.10 (4H, m).

cis-N-(4-{[1-Acetyl-6chloro-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]amino}-phenyl)acetamide (Compound No. 61 Table I).

¹H NMR CDCl₃: δ 7.33–6.91 (5H, m); 6.63–6.54 (2H, d); 4.86 (1H, br s); 4.12 (1H, br d); 3.71 (1H, br s); 2.69–2.59 (1H, m); 2.17 (3H, s); 2.14 (3H, s); 1.32–1.09 (4H, m).

cis-4-[{1-Acetyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl}amino]-benzoic acid methyl ester (Compound No. 62 Table I).

¹H NMR CDCl₃: δ 7.88 (2H, d); 7.33–7.12 (4H, m); 6.60 (2H, d); 4.93 (1H, br d); 4.34–4.20 (2H, m); 3.85 (3H, s); 2.72–2.63 (1H, m); 2.19 (3H, s); 1.31 (1H, q); 1.16 (3H, d).

cis-N-(4-{[1-Acetyl-6-methoxy-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]amino}-phenyl)acetamide (Compound No. 63 Table I).

¹H NMR CDCl₃: δ 7.33–7.25 (2H, m); 7.12–6.77 (4H, m); 6.61 (2H, d); 4.92 (1H, br s); 4.15 (1H, dd); 3.75 (3H, s); 2.69–2.59 (1H, m); 2.16 (6H, s); 1.30–1.07 (4H, m).

cis-1-Acetyl-1,2,3,4-tetrahydro-6-methoxy-2-methyl-N-[4-(methylsulfonyl)phenyl]-4-quinolinamine (Compound No. 64 Table I).

¹H NMR CDCl₃: δ 7.73 (2H, d); 7.08 (1H, br d); 6.82 (1H, dd); 6.73 (1H, br d); 6.67 (2H, d); 4.95 (1H, br s); 4.36–4.20 (2H, m); 3.74 (3H, s); 3.01 (3H, s); 2.69–2.60 (1H, m); 2.17 (3H, s); 1.36–1.22 (1H, m); 1.14 (3H, d).

1-[(2S*,4R*)-4-(4-benzoylanilino)-6-bromo-2-methyl-3,4-dihydro-1(2H)-quinolinyl]-1-ethanone (Compound No. 65 Table I). [α]_(D) ²⁰=132° (c=0.8, CH₂Cl₂).

¹H NMR MeOD (two protons is obscured by the H₂O-signal): δ 7.73–7.64 (4H, m); 7.60–7.44 (4H, m); 7.31 (1H, dd); 7.24 (1H, br d); 6.73 (2H, d); 4.39 (1H, dd); 2.72–2.63 (1H, m); 2.19 (3H, s); 1.43–1.30 (1H, m); 1.16 (3H, d).

cis-1-Acetyl-1,2,3,4-tetrahydro-N-(4-methoxyphenyl)-2-methyl-6-(4-morpholinyl)-4-quinolinamine (Compound No. 66 Table I).

¹H NMR CDCl₃: δ 7.03 (1H, br d); 6.96 (1H, br d); 6.83–6.76 (3H, m); 6.63 (2H, d); 4.88 (1H, br s); 4.10 (1H, dd); 3.83 (4H, t); 3.77 (3H, s); 3.51 (1H, br s); 3.17–3.04 (4H, m); 2.66–2.58 (1H, m); 2.16 (3H, s); 1.26–1.11 (4H, m).

cis-4-{[1-Acetyl-2-methyl-6-(4-morpholinyl)-1,2,3,4-tetrahydro-4-quinolinyl]-amino}benzonitrile (Compound No. 67 Table I).

¹H NMR CDCl₃: δ 7.45 (2H, d); 7.09 (1H, br d); 6.86 (1H, dd); 6.78 (1H, br s); 6.63 (2H, d); 4.91 (1H, br s); 4.27–3.92 (2H, m); 3.83 (4H, t); 3.16–3.01 (4H, m); 2.68–2.58 (1H, m); 2.18 (3H, s); 1.30 (1H, q); 1.14(3H, d).

cis-1-Acetyl-1,2,3,4-tetrahydro-2-methyl-6-(4-morpholinyl)-N-phenyl-4-quinolinamine (Compound No. 68 Table I).

¹H NMR CDCl₃: δ 7.25–6.64 (8H, m); 4.90 (1H, br s); 4.19 (1H, dd); 3.82 (4H, t); 3.19–3.02 (4H, m); 2.67 (1H, m); 2.17 (3H, s); 1.33–1.10 (4H, m).

cis -4-[{1-Acetyl-2-ethyl-1,2,3,4-tetrahydro-4-quinolinyl}amino]-benzoic acid methyl ester (Compound No. 69 Table I).

¹H NMR CDCl₃: δ 7.88 (2H, d); 7.32–7.07 (4H, m); 6.59 (2H, d); 4.86 (1H, br s); 4.30 (1H, dd); 3.85 (3H, s); 2.72–2.62(1H, m); 2.18 (3H, s); 1.74–1.26 (3H, m); 0.86 (3H, t).

cis-1-Acetyl-1,2,3,4-tetrahydro-N,2-diphenyl-4-quinolinamine (Compound No. 70 Table I).

¹H NMR CDCl₃: δ 7.43–7.14 (11H, m); 6.80 (1H, t); 6.70 (2H, d); 5.81 (1H, br s); 4.42 (1H, dd); 3.85 (1H, br s); 2.93–2.84 (1H, m); 2.23 (3H, s); 1.78 (1H, q).

cis-1-Acetyl-1,2,3,4-tetrahydro-2-methyl-6-(methylthio)-N-phenyl-4-quinolinamine (Compound No. 72 Table I).

¹H NMR CDCl₃: δ 7.30–6.99 (5H, m); 6.76 (1H, t); 6.64 (2H, d); 4.87 (1H, br s); 4.24–4.12 (1H, m); 3.75 (1H, br d); 2.70–2.58 (1H, m); 2.38 (3H, s); 2.16 (3H, s); 1.33–1.05 (4H, m).

cis-1-Acetyl -1,2,3,4-tetrahydro-2-methyl-6-(methylsulfonyl)-N-phenyl-4-quinolinamine (Compound No. 73 Table I).

¹H NMR CDCl₃: δ 7.96–7.88 (2H, m); 7.39 (1H, d); 7.22 (2H, t); 6.80 (1H, t); 6.65 (2H, d); 4.90–4.78 (1H, m); 4.32–4.23 (1H, m); 3.83 (1H, br d); 3.03 (3H, s); 2.79–2.69 (1H, m); 2.26 (3H, s); 1.41–1.29 (1H, m); 1.21 (3H, d).

(2S*,4R*)-1-Acetyl -1,2,3,4-tetrahydro-6-iodo-2-methyl-N-phenyl-4-quinolinamine (Compound No. 74 Table I). [α]_(D) ²⁰=309° (c=0.6, CH₃Cl).

¹H NMR CDCl₃: δ 7.67 (1H, br s); 7.63 (1H, dd); 7.23 (2H, dt); 6.90 (1H, br d); 6.79 (1H, t); 6.64 (2H, d); 4.86 (1H, br d); 4.17 (1H, br d); 3.74 (1H, br s); 2.69–2.59 (1H, m); 2.19 (3H, s); 1.35–1.22 (1H, m); 1.16 (3H, d).

(2S,4R)-1-Acetyl-6-bromo-2-methyl-N-phenyl-1,2,3,4-tetrahydro-4-quinolinamine (Compound No. 75 Table I). [α]_(D) ²⁰=278° (c=0.11, CH₂Cl₂).

¹H NMR CDCl₃: δ 7.48 (1H, m); 7.43 (1H, dd); 7.28–7.18 (2H, m), 7.08–6.98 (1H, d); 6.79 (1H, t); 6.64 (2H, d); 4.92–4.80 (1H, s); 4.18 (1H, dd); 3.90–3.70 (1H, s); 2.71–2.60 (1H, m); 2.18 (3H, s); 1.32–1.19 (1H, m); 1.17 (3H, d).

trans-1-Acetyl -1,2,3,4-tetrahydro-2-methyl-N-phenyl-4-quinolinamine (Compound No. 1 Table II).

¹H NMR CDCl₃: δ 7.41 (1H, dd); 7.32–7.12 (5H, m); 6.74–6.62 (3H, m); 4.92 (1H, d); 4.61 (1H, d); 3.85 (1H, s); 2.56–2.46 (1H, m); 2.18 (3H, s); 1.81–1.72 (1H, m); 1.20 (3H, d).

trans-1-Acetyl -1,2,3,4-tetrahydro-4-[[4-(methoxycarbonyl)phenyl]amino]-2-methyl-6-quinolinecarboxylic acid methyl ester (Compound No. 18 Table II).

¹H NMR CDCl₃: δ 8.10 (1H, d); 7.98 (1H, dd); 7.86 (2H, d); 7.37 (1H, d); 6.62 (2H, d); 4.92–4.84 (1H, m); 4.76–4.71 (1H, t); 4.40–4.30 (1H, s br); 3.91 (3H, s); 3.84 (3H, s); 2.50–2.42 (1H, m); 2.21 (3H, s); 1.96–1.88 (1H, m); 1.22 (3H, d).

trans-1-Acetyl -N-(2-chlorophenyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinamine (Compound No. 21 Table II).

¹H NMR CDCl₃: δ 7.45–7.18 (6H, m), 6.86 (1H, d); 6.62 (1H, dd); 4.99–4.92 (1H, m); 4.76–4.60 (2H, m); 2.65–2.58 (1H, m); 2.20 (3H, s); 1.81–1.76 (1H, m); 1.01 (3H, d).

trans-1-Acetyl-N-(4-bromophenyl)-1,2,3,4-tetrahydro-2-methyl-4-quinolinamine (Compound No. 24 Table II).

¹H NMR CDCl₃: δ 7.42 (6H, m); 6.53 (2H, d); 5.0–4.85 (1H, d br); 4.55 (1H, t); 2.58–2.49 (1H, m); 2.18 (3H, s); 1.80–1.72 (1H, m); 1.19 (3H, d).

cis-1-Acetyl-1,2,3,4-tetrahydro-2-methyl-N-(2-pyrazinyl)-4-quinolinamine (Compound No. 1 Table III).

¹H NMR CDCl₃: δ 8.05–7.99 (2H, m); 7.92 (1H, d); 7.38–7.15 (4H, m); 5.01–4.90 (1H, m); 4.90–4.82 (1H, m); 4.72 (1H, d); 2.73–2.62 (1H, m); 2.18 (3H, s); 1.38–1.25 (1H, m); 1.19 (3H, d).

cis-1-Acetyl -6-chloro-1,2,3,4-tetrahydro-2-methyl-N-(2-pyrazinyl)-4-quinolinamine (Compound No. 2 Table III).

¹H NMR CDCl₃: δ 8.04–8.01 (2H, m); 7.93 (1H, d); 7.28 (1H, dd); 7.23 (1H, dd); 7.11 (1H, d); 4.98–4.80 (2H, m); 4.80–4.78 (1H, m); 2.70

cis-1-Acetyl-1,2,3,4-tetrahydro-2-methyl-N-(4-pyridinyl)-4-quinolinamine (Compound No. 3 Table III).

−2.62 (1H, m); 2.18 (3H, s); 1.39–1.24 (1H, m); 1.19 (3H, d).

¹H NMR CD₃OD: δ 8.27 (2H, d); 7.48–7.45 (2H, m); 7.38–7.29 (1H, m); 7.00 (2H, d); 6.61 (1H, d); 5.41 (1H, dd); 5.02–4.88 (1H, m); 2.93–2.82 (1H, m); 2.21 (3H, s); 2.18–2.00 (1H, m); 1.35 (3H, d).

BIOLOGICAL ASSAY

The ability of the compounds described herein to inhibit STAT6 signaling pathway is manifested in their ability to inhibit STAT6 driven reporter gene activity.

The cytokine-responsive human cell line U937 were transfected with a reporter gene plasmid consisting of an interluekin 4 (IL-4) responsive promoter driving the heterologous firefly gene for luciferase. The reporter gene plasmid also contained a gene for neomycin resistance. The IL-4 responsive promoter were constructed by four oligomerized combined C/BEPβ and STAT6 binding sites with the nucleotide sequence GTTGCTCAATCGACTTCCCAAGAA in close contact with a TATA-box. Cells with a stable integration of the reporter gene plasmid were selected by cultivation in neomycin. Such transfected cells were used for IL-4 induction by adding 10 ng/ml recombinant human IL-4 to 0.5–1×10⁶ cells per ml. IL-4 induction were carried out for 4–5 h. Thereafter the cells were lysed and luciferase activity determined by using standard techniques. Numbers measured are the mean fold induction (fold induction for U937 is defined as the luciferase response in an IL-4 treated U937 cell sample divided by the luciferase response in an untreated U937 cell sample). Typically, IL-4 stimulation gave 15–20 fold induction of the luciferase response. Compounds were added 5 min before IL-4 when tested in the reporter gene assay. Compound effect was expressed as the concentration of compound giving 50 percent inhibition (IC50) of the luciferase response to addition of IL-4. The results from compound testing are shown in Table IV.

TABLE IV Inhibition of STAT6-driven reporter gene activity Compound No 27 Table I No 36 Table I No 74 Table I IC50 μM 0.80 0.43 0.18 

1. compound of formula (I):

wherein: L is CH₂, O or S; n is 0 or 1; W, Y and Z are, independently hydrogen, cyano, nitro, halogen, N₃, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkylthio, C₃₋₆ cycloalkyl, CO₂H, CO₂(C₁₋₆ alkyl), CONR⁵R⁶, COR¹⁰ SO₂R¹², methylenedioxy, NHCOR¹¹ or heterocyclyl; R² is aryl or heteroaryl optionally substituted by cyano, nitro, halogen, N₃, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkylthio, C₃₋₆ cycloalkyl, CO₂H, CO₂(C₁₋₆ alkyl), CONR¹³ R¹⁴, COR¹⁵, SO₂R¹⁶, methylenedioxy, NHCOR¹⁷ or heterocyclyl; R³ is C₁₋₄ alkyl or C₁₋₄ haloalkyl; R⁴ is CO(C₁₋₄ alkyl) or CO(C₁₋₄ haloalkyl); X is O, S, SO, SO₂, CR⁷R⁸or NR⁹; R⁵, R⁶, R⁷, R⁸, R¹³ and R¹⁴ are, independently, hydrogen or C₁₋₆ alkyl; R⁹ is hydrogen, C₁₋₆ alkyl or CO(C₁₋₄ alkyl); R¹⁰, R¹¹, R¹², R¹⁵, R¹⁶ and R¹⁷ are, independently, C₁₋₆ alkyl or phenyl; or a pharmaceutically acceptable salt thereof; or a solvate thereof; provided that the compound of formula (I) is not a compound of formula (Iz): (Iz)

wherein R^(1b) R^(1d) R^(1c) R^(4′) R² R⁹ H H H n-butyl C₆H₅ H H H H n-propyl C₆H₅ COCH₃ H H H n-propyl C₆H₅ H H H H Ethyl C₆H₅ H Br H H Methyl C₆H₅ COCH₃ Methyl H H Methyl 4-CH₃—C₆H₄ H Methyl Methyl H Methyl 2,4-(CH₃)₂—C₆H₃ H H H H Methyl C₆H₅ H NO₂ H H Methyl 4-NO₂—C₆H₄ COCH₃ NO₂ H H Methyl C₆H₅ COCH₃ Cl H H Methyl C₆H₅ COCH₃ H H H Methyl C₆H₅ COCH₃ H H H Methyl 2,4-Br₂—C₆H₃ COCH₃ in free base or unsolvated form.


2. A compound of formula (Ia):

wherein Z, R³, R⁴ and X are as defined in claim 1 , and R^(2c) is hydrogen, cyano, nitro, halogen, N₃, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkylthio, C₃₋₆ cycloalkyl, CO₂H, CO₂(C₁₋₆ alkyl), CONR¹³R¹⁴, COR¹⁵, SO₂R¹⁶, methylenedioxy, NHCOR¹⁷ or heterocyclyl; wherein R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are as defined in claim 1; or a pharmaceutically acceptable salt thereof; or a solvate thereof.
 3. A compound as claimed in claim 1 wherein X is NH.
 4. A compound as claimed in claim 1 wherein R³ is methyl.
 5. A compound as claimed in claim 1 wherein R⁴ is C(O)CH₃.
 6. A compound as claimed in claim 1 wherein R² is phenyl para-substituted by C(O)₂CH₃, iodo, N₃, bromo, methyl, C(O)₂CH₂CH₃, cyano or methoxy.
 7. Processes for the preparation of a compound of formula (I) as claimed in claim 1 by reacting a compound of formula (II):

with acetic anhydride in the presence of a base at room temperature.
 8. A pharmaceutical composition which comprises a compound of the formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof or solvate thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier.
 9. A compound as claimed in claim 1, wherein X is NH; R³ is methyl; and R⁴ is C(O)CH₃.
 10. A compound as claimed in claim 9, wherein R² is phenyl para-substituted by C(O)₂CH₃, iodo, N₃, bromo, methyl, C(O)₂CH₂CH₃, cyano or methoxy.
 11. A pharmaceutical composition as claimed in claim 8, wherein the compound is of the formula (I) as claimed in claim 10, or a pharmaceutically acceptable salt thereof of solvate thereof.
 12. A pharmaceutical composition as claimed in claim 8, wherein the compound is of the formula (I) as claimed in claim 10, or a pharmaceutically acceptable salt thereof of solvate thereof.
 13. A compound as claimed in claim 1, wherein the compound is a compound of Table I, Table II, or Table III.
 14. A method for making a pharmaceutical composition as claimed in claim 8, comprising mixing a compound of formula (I) as claimed in claim 1 with a pharmaceutically acceptable adjuvant, diluent or carrier. 